icatibant and Ventricular-Dysfunction--Left

Diabetic cardiomyopathy includes fibrosis. Kallikrein (KLK) can inhibit collagen synthesis and promote collagen breakdown. We investigated cardiac fibrosis and left ventricular (LV) function in transgenic rats (TGR) expressing the human kallikrein 1 (hKLK1) gene in streptozotocin (STZ) -induced diabetic conditions. Six weeks after STZ injection, LV function was determined in male Sprague-Dawley (SD) rats and TGR(hKLK1) (n=10/group) by a Millar tip catheter. Total collagen content (Sirius Red staining) and expression of types I, III, and VI collagen were quantified by digital image analysis. SD-STZ hearts demonstrated significantly higher total collagen amounts than normoglycemic controls, reflected by the concomitant increment of collagen types I, III, and VI. This correlated with a significant reduction of LV function vs. normoglycemic controls. In contrast, surface-specific content of the extracellular matrix, including collagen types I, III, and VI expression, was significantly lower in TGR(hKLK1)-STZ, not exceeding the content of SD and TGR(hKLK1) controls. This was paralleled by a preserved LV function in TGR(hKLK1)-STZ animals. The kallikrein inhibitor aprotinin and the bradykinin (BK) B2 receptor antagonist icatibant reduced the beneficial effects on LV function and collagen content in TGR(hKLK1)-STZ animals. Transgenic expression of hKLK1 counteracts the progression of LV contractile dysfunction and extracellular matrix remodeling in STZ-induced diabetic cardiomyopathy via a BK B2 receptor-dependent pathway.

Topics: Animals; Animals, Genetically Modified; Aprotinin; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiomyopathies; Collagen; Diabetes Mellitus, Experimental; Humans; Kallikreins; Male; Myocardium; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Streptozocin; Ventricular Dysfunction, Left

ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (e.g remodelling, diastolic dysfunction). We have previously reported that the ACE inhibitor captopril induces selective left ventricular (LV) relaxant effects in the isolated ejecting guinea pig heart. The aim of the present study was to further investigate the mechanism of the captopril-induced changes in early LV relaxation by comparing the effects of two sulphydryl and two non-sulphydryl containing ACE inhibitors in the same experimental preparation. Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter transducer inserted in the LV cavity. The sulphydryl-containing ACE inhibitors captopril and zofenaprilat enhanced early LV relaxation, whereas the non-sulphydryl-containing ACE inhibitors lisinopril and quinaprilat did not. The effects of captopril and zofenaprilat were attenuated both by the nitric oxide-scavenger haemoglobin and the bradykinin B2-kinin receptor antagonist HOE 140. Neither the oxygen free-radical scavenger superoxide dismutase nor the sulphydryl-containing compound N-acetyl cysteine administered together with lisinopril had any effect on LV relaxation. These data demonstrate that inhibition of intra-cardiac ACE activity may acutely modulate LV relaxation through increased activity of the bradykinin-nitric oxide pathway. The presence of a sulphydryl group on the relevant ACE inhibitor appears to be essential for this LV relaxant effect.

Topics: Acetylcysteine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Diastole; Female; Free Radical Scavengers; Guinea Pigs; Heart Ventricles; Hemoglobins; Isoquinolines; Lisinopril; Male; Muscle Relaxation; Nitric Oxide; Receptor, Bradykinin B2; Simethicone; Stroke Volume; Sulfhydryl Compounds; Superoxide Dismutase; Systole; Tetrahydroisoquinolines; Ventricular Dysfunction, Left